Mammalian Development

 

Understanding idiopathic disease using mouse models

We are using the mouse model as a way to understand the biology behind two disorders who etiology is poorly understood.  Our collaborators at the Texas Scottish Rite Hospital for Children (TSRHC) have identified several genes associated with club foot and adolescent idiopathic scoliosis (AIS).  

AIS occurs between the ages of 11- 18 years in association with puberty and can progressively worsen over time. Over 90% of the cases are female indicating a strong sex-basis in scoliosis development.

Clubfoot is a common congenital birth defect that affects around 1 in 1000 children, with a higher incidence of 7 in 1000 Maori.  

The biology underlying AIS and clubfoot is poorly understood however several genes have been  linked to these diseases as a result of genome-wide association studies (GWAS) and exome sequencing studies. 

We are using a combination of ChIP-seq and RNA-seq to begin to understand the role of these genes in the normal development of the effected tissues and thus the biological pathways disrupted by mutations in these genes.  This has allow us to develop several hypothesis that explain the biology behind idiopathic club foot and AIS which we are now testing.

The long-term goal of this research is to aid the development of evidence-based treatment for progressive disorders.

 

 Collaborators:
Prof. Carol Wise (TSRHC), Dr Jonathan Rios (TSRHC), Prof. Stephen Robertson (Otago), A/P Greg Anderson (Otago).

 

 

 

Sex-dimorphic brain development

This research programme is aimed at understanding how the sex of an individual effects differentiation of the brain, and how this is associated with behavior or risk of neurological damage and disease. 

We aim to reveal the finer biological details that underlie sex-specific differences in brain development during early embryonic development, and how this may relate to the sex bias presentation of many neurological disorders.  

Male and female neuronal development is sexually dimorphic; the male brain develops at a slower rate than the female brain. There is a strong sex bias in many common brain disorders and in responses to brain injury. Studies focused on brain anatomy have failed to determine the underlying features of susceptibility to these complex disorders.    

Do these differences in growth and development of the male and female brain reflect and underlie the sex-dimorphic responses to neurological injury and disease, particularly those affecting infants and adolescents?

 Collaborators: Prof. Ian McLennan (Otago)

 

Gene regulation during development: The role of RNA polymerase II pausing

Proximal-promoter pausing by RNA polymerase II is a key rate-limiting step in transcription initiation.  Recent genome-wide studies using chromatin-immunoprecipitation for bound RNA-polII have shown that promoter-pausing occurs for a number of genes, particularly developmental genes.  

This stalling is believed to be a mechanism of gene regulation, causing RNA-polII to be paused near a promoter region, ready to respond to environmental or developmental cues.  Two transcription elongation factors DSIF and NELF control promoter stalling of RNA-polII.

Our laboratory has uses gonadal and head/brain development as a model to examine gene regulation during development. We are using a combination of ChIP-seq, qRT-PCR, in situ hybridization and explant culture to determine if RNA-polII pausing does play an important gene regulatory role in development.

 

Collaborators: A/P Christine Jasoni (Otago).

 

Early development of the genital ridge and disorders of sex development. 

Lhx9 gene expression in the developing urogenital ridge

The developing foetal gonad is unique as it has the potential to form two different organs, an ovary or a testis, from the same progenitor tissue.  Reproductive development is fundamental to all animals, but to date only a handful of genes have been shown to be required for the formation of the genital ridge from which the gonads develop.  Unfortunately, disorders of sex determination (DSD) are among the more common birth defects, occurring in 7 cases per 1000 births in New Zealand.  Furthermore, there is a strong association between DSD and both testicular and ovarian cancer.  At least 30% of children with gonadal dysgenesis develop gonadal neoplasms that can go on to produce malignant germ cell tumours within their first 10 years.  Mutation or misregulation of genes involved in sex determination and gonad development are also associated with DSD-associated tumours, indicating a relationship between aberrant development of the gonad and increased risk of tumour formation.

Little is understood about the dynamics of genital ridge formation, and how outgrowth and proliferation of the genital ridge is controlled and maintained during gonad formation.   We are using next-generation sequencing technologies to determine the gene networks and pathways that underlie embryo gonad development.